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Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

Bottom Line: Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food.Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada.Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.

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Model predictions for rats.Blood serum (venous blood) concentration of ZEA for 8 mg/kg BW of (a) injected dose, and (b) oral dose over a period of 24 hours; PBTK model predictions (red line) compared with in vivo measurements in rats from Shin et al.[34].
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pone-0113632-g007: Model predictions for rats.Blood serum (venous blood) concentration of ZEA for 8 mg/kg BW of (a) injected dose, and (b) oral dose over a period of 24 hours; PBTK model predictions (red line) compared with in vivo measurements in rats from Shin et al.[34].

Mentions: The PBTK model developed for rats was implemented for 3 different dosage routes in 8–10 week old Sprague-Dawley rats and the model predictions over time were compared with in vivo measurements in rats from Shin et al.[31], [34]. Intravenous (IV) injection presents the least complicated situation with respect to biodistribution of a chemical. Partitioning of the chemical between various tissues and blood, and excretion from the body through various routes can be studied without the complexities of gastro-intestinal absorption. Data from in vivo IV injection studies by Shin et al.[34] were used to parametrize and evaluate the PBTK model. Using the data, all biochemical parameters except for those relevant to the GI tract were estimated. Comparisons of results for this dosage route are shown for venous blood serum in Fig. 7(a). Additional results for various other tissues and comparisons for multiple IV doses are included in S1 Information (Figure S2). The kinetics of ZEA in blood rapidly increases instantaneously after the IV dose and then decreases exponentially as also observed in the in vivo measurements. The study also focussed on the effects of oral ingestion of ZEA and ZAL in rats. The ZEA oral ingestion study was evaluated with data from Shin et al.[34], where Sprague-Dawley rats were given a single dose (8 mg/kg body weight) by po gavage. Fig. 7(b) shows the venous concentration of ZEA in rats after the single oral dose over a 24 hour period compared with in vivo data from Shin et al.. The model successfully captures the two consecutive peaks in venous blood concentration subsequent to oral dosage. The secondary peak in venous concentration after oral dosage was reported previously in multiple species [31], [52], [53] and may be due to biliary recirculation or temporary storage in tissues and subsequent vascular recirculation. The in vivo data for rats helps to evaluate the model and build confidence for its use as a tool for planning and validating future in vivo experiments. The model also provides initial estimates for various biochemical parameters for the PBTK model for human subjects for which in vivo data are not easily available. The model was further evaluated with in vivo data from an intravenous infusion study [31], to compare steady-state and long-term dynamics of the PBTK model developed for rats. Results are presented in S1 Information (Figure S3) for comparisons with two different rates of infusion.


Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

Model predictions for rats.Blood serum (venous blood) concentration of ZEA for 8 mg/kg BW of (a) injected dose, and (b) oral dose over a period of 24 hours; PBTK model predictions (red line) compared with in vivo measurements in rats from Shin et al.[34].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256163&req=5

pone-0113632-g007: Model predictions for rats.Blood serum (venous blood) concentration of ZEA for 8 mg/kg BW of (a) injected dose, and (b) oral dose over a period of 24 hours; PBTK model predictions (red line) compared with in vivo measurements in rats from Shin et al.[34].
Mentions: The PBTK model developed for rats was implemented for 3 different dosage routes in 8–10 week old Sprague-Dawley rats and the model predictions over time were compared with in vivo measurements in rats from Shin et al.[31], [34]. Intravenous (IV) injection presents the least complicated situation with respect to biodistribution of a chemical. Partitioning of the chemical between various tissues and blood, and excretion from the body through various routes can be studied without the complexities of gastro-intestinal absorption. Data from in vivo IV injection studies by Shin et al.[34] were used to parametrize and evaluate the PBTK model. Using the data, all biochemical parameters except for those relevant to the GI tract were estimated. Comparisons of results for this dosage route are shown for venous blood serum in Fig. 7(a). Additional results for various other tissues and comparisons for multiple IV doses are included in S1 Information (Figure S2). The kinetics of ZEA in blood rapidly increases instantaneously after the IV dose and then decreases exponentially as also observed in the in vivo measurements. The study also focussed on the effects of oral ingestion of ZEA and ZAL in rats. The ZEA oral ingestion study was evaluated with data from Shin et al.[34], where Sprague-Dawley rats were given a single dose (8 mg/kg body weight) by po gavage. Fig. 7(b) shows the venous concentration of ZEA in rats after the single oral dose over a 24 hour period compared with in vivo data from Shin et al.. The model successfully captures the two consecutive peaks in venous blood concentration subsequent to oral dosage. The secondary peak in venous concentration after oral dosage was reported previously in multiple species [31], [52], [53] and may be due to biliary recirculation or temporary storage in tissues and subsequent vascular recirculation. The in vivo data for rats helps to evaluate the model and build confidence for its use as a tool for planning and validating future in vivo experiments. The model also provides initial estimates for various biochemical parameters for the PBTK model for human subjects for which in vivo data are not easily available. The model was further evaluated with in vivo data from an intravenous infusion study [31], to compare steady-state and long-term dynamics of the PBTK model developed for rats. Results are presented in S1 Information (Figure S3) for comparisons with two different rates of infusion.

Bottom Line: Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food.Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada.Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.

Show MeSH
Related in: MedlinePlus